# Investigating the synaptic pathology of Autism

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $545,347

## Abstract

PROJECT SUMMARY
Genetic mutations that confer autism risk often occur in genes that are expressed at the glutamate synapse.
The protein products of these genes form a highly interconnected protein interaction network (PIN), and
represent attractive therapeutic targets since they are expressed throughout the lifespan and can be acutely
targeted with small molecule drugs. However, the dynamic, network-scale behavior of this PIN in normal or
disease states is poorly understood. Here, we apply a novel PIN-mapping technology, quantitative multiplex
co-immunoprecipitation, to explore the input-output relationships of an autism-linked PIN at the glutamate
synapse as it responds to physiological inputs. Our target system is a 20-member PIN, consisting of glutamate
receptors, scaffolds, and signal transduction molecules; mutations in the genes encoding all target proteins
have been genetically linked to autism. We first show that, in wild-type animals, our target PIN changes its
pattern of co-associations in a stereotyped manner in response to acute stimulation with KCl or glutamate,
using cultured neurons or acute slices. We then model the input-output relationships of the PIN system, and
demonstrate that the PIN produces specific, recognizable signatures in response to stimulation through the
mGluR or NMDA receptors. In the context of physiological glutamate stimulation, the PIN integrates the two
inputs to produce a coordinated cellular response- potentiation or de-potentiation. Based on these and other
preliminary observations and published data, we propose that mutations that contribute to autism risk disrupt
information flow through this PIN, such that the balance between LTP-like potentiation and LTD-like
depotentiaion is altered, ultimately leading to an organism-level imbalance between excitation and inhibition.
We will test this hypothesis by modeling the PIN response to mGluR or NMDA stimulation in three distinct,
well-characterized animal models of autism- the Fragile X knockout, Shank3 knockout, and Ube3a
overexpressing models. We will characterize the input-output relationships for mGluR or NMDA stimulation,
and mathematically model their integration using a vector transformation model in principal component space.
We will define specific mechanisms by which autism-linked mutations disrupt either input-output relationships,
or disrupt signal integration in the context of physiological stimulation. In addition, we will treat two of our
animal models (Shank3 and Fragile X) with drugs that have been previously demonstrated to rescue autism-
like behaviors. We will model the response of the PIN to the drug with or without concurrent stimulation to
define a PIN signature associated with behavioral rescue. In summary we propose to (1) define normal
information flow through a PIN consisting of the protein products of autism-liked genes; (2) define how
information flow is disrupted in mouse models of autism, with the goal of understanding the system...

## Key facts

- **NIH application ID:** 10292984
- **Project number:** 5R01MH113545-05
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Stephen Edward Paucha Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $545,347
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10292984

## Citation

> US National Institutes of Health, RePORTER application 10292984, Investigating the synaptic pathology of Autism (5R01MH113545-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10292984. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*